Abstract Many individuals with Parkinson disease (PD) experience a reduction in mobility with gait difficulties that include impaired turning that can trigger freezing. These turning difficulties are particularly critical since falls during turning carry an eightfold greater risk of hip fracture compared to falls during straight line walking. Furthermore, people with PD are over three times more likely to sustain a hip fracture than age-matched cohorts without PD, and the cost of care for hip fractures in individuals with PD is approximately $192 million per year. Given the personal and economic impacts associated with falls, it is critical that we develop interventions to reduce falling risk during turning among those with PD. Mechanisms underlying impaired turning in PD are not well understood. We think that: 1) individuals with PD who have difficulty turning will show impaired ability to rapidly switch movement directions of not just the limbs but also the eyes and 2) eye movement impairments may contribute to difficulties with turning. Through use of kinematic and videooculographic analyses, along with a rotating circular treadmill and optokinetic stimulation, we will determine: 1) whether individuals with PD who have turning difficulty show impairments in ability to rapidly switch movement direction of the eyes and lower limbs, and 2) whether deficits in eye movement control contribute to turning difficulties in PD. The long-term objective of the proposed research is to better understand the relationship between oculomotor and limb motor control deficits in individuals with PD and how these deficits relate to impaired turning. Using the knowledge gained, we aim to develop innovative gait rehabilitation approaches for individuals with PD with the ultimate goal of reducing falls and hip fractures in this population. Earhart, Gammon M. R01-HD056015-01A2 Revised for ARRA Consideration Modified Specific Aims EARHART, GAMMON M. 1R01HD056015-O1A2, REVISION FOR ARRA CONSIDERATION STATEMENT REGARDING REVISION OF GRANT FOR POSSIBLE 2-YEAR ARRA AWARD The revised version of this application to be considered for two years of ARRA funding includes only Aims 1 and 2 of the original application. These Aims include two distinct studies that could be completed in a two-year period of time with the addition of another person, most likely a graduate student or postdoctoral fellow, to the research team. I do not anticipate that this will greatly change the originally requested budget, however, as some equipment requests in the original grant were relevant only to Aim 3. Aim 3 of the original application, which included three distinct studies to develop and test interventions to address the problems studied in Aims 1 &2, would be eliminated as it is not amenable to completion in such a short period of time. As Aim 3 would be eliminated in the revised version, the equipment items originally requested for Aim 3 would no longer be needed. The money that would have gone toward equipment for Aim 3 would instead be used to fund an additional person to aid in the timely completion of Aims 1 &2. If awarded a two-year ARRA award, we would plan to submit an application for a competitive renewal using the data gathered during the first portion of the ARRA award to support this submission. Future directions for the work could include: 1) revisiting Aim 3 to develop and test interventions to address eye movement impairments and turning difficulties and reduce fall risk in individuals with PD, 2) exploration of the relationship of eye movements to other problems related to PD, such as freezing of gait which is often triggered by visual cues in the environment and can often be relieved by different visual cues, or 3) performance of similar studies in individuals with PD who have deep brain stimulators implanted in the subthalamic nucleus. Testing of these individuals on and off stimulation could provide important insights into the mechanisms underlying impairments of eye movements and gait in individuals with PD. In short, we envision the proposed studies as the first steps in a longer line of research that we will continue to actively pursue in the coming years. REVISED SPECIFIC AIMS Parkinson disease (PD) is a progressive neurodegenerative condition that affects nearly 1.5 million people in the United States. Many individuals with PD experience a reduction in mobility with problems that include difficulty turning. Turning difficulties can lead to freezing of gait, falls, fear of falling, and social withdrawal (Bloem et al. 2004). Falls during turning are eight times more likely to result in hip fracture than falls during straight walking (Cumming &Klineberg 1994) and individuals with PD are 3.2 times more likely to sustain a hip fracture than people of similar age without PD. The annual cost of care for hip fractures in PD is approximately $192 million (Bacon, 1996, Melton et al. 2006). Given the personal and financial costs associated with this problem, it is clear that strategies are needed that address turning difficulties to reduce falls and fractures. We hypothesize that: 1) the mechanism underlying turning difficulty may be a general deficit in the ability to select and execute motor programs required to switch directions, 2) this mechanism affects not just body movements but also eye movements, and 3) impaired eye movements contribute to turning problems in people with PD. The goal of this proposal is to determine whether eye movement deficits contribute to gait difficulties in PD. Through use of kinematic and oculographic analyses we will address the following specific aims: Specific Aim 1: To determine whether individuals with PD who have turning difficulty also have difficulty switching movement direction during movements of the eyes, lower limbs, or eyes and lower limbs simultaneously. The mechanisms underlying turning difficulty are poorly understood. We think turning difficulty may reflect a general deficit in the ability to select and execute motor programs required to switch directions. We expect this deficit to affect ability to switch movement direction of the eyes as well as the lower limbs. Subjects with PD who have turning difficulty and matched controls will perform eye, lower extremity, or simultaneous eye and lower extremity movements to specific targets and be asked to rapidly switch movement directions during these tasks. H1a: Time to switch movement direction of the eyes and lower limbs will be longer in those with PD than in controls for all conditions. H1b: Time to switch movement direction of the eyes and limbs will be correlated and, for the combined eye-limb movements, pauses during direction change will affect both the eyes and the limbs at the same time, indicating a similar amount of decline in direction switch ability between these body parts and a potential common control mechanism for the eyes and limbs. Specific Aim 2a: To determine whether eye movements during turning are impaired in individuals with PD who have difficulty turning during walking. Turns are normally initiated following a top-down sequence EARHART, GAMMON M. 1R01HD056015-O1A2, REVISION FOR ARRA CONSIDERATION of rotations that begins with a saccade in the direction of the turn, followed by subsequent rotations of the head, trunk, pelvis, and lower extremities. Subjects with PD who have turning difficulty and matched controls will perform turning movements during walking. H2a: Participants with PD will demonstrate slower, smaller saccades at turn initiation and will make many small saccades while controls will make a few large saccades during turns. Specific Aim 2b: To determine whether characteristics of the saccade that initiates a turn are predictive of ensuing turn performance. We will analyze data from Aim 2a to determine whether characteristics of the saccade that initiates a turn are predictive of other turn characteristics, such as time to turn. We expect that trials where the turn is initiated with a saccade of relatively greater amplitude will be characterized by less turning difficulty as evidenced by shorter time required to execute the turn. Trials initiated by slow, small saccades will be characterized by more turning difficulty as evidenced by longer time required to execute the turn. H2b: The amplitude,velocity, and latency of the saccade initiating a turn will be predictive of the time required to execute the turn. We expect turns that are initiated with slower, smaller, and later saccades to take longer.